Coherence of co-familial phenotypes in schizophrenia: Craniofacial dysmorphology, though disorder, and smooth pursuit eye movements

80 in the treatment of schizophrenia has been demonstrated by combining the c~1-antagonist, prazosin, with haloperidol to produce superior effects similar to those of atypical antipsychotics. Genetic mutations in the C~lA-adrenoceptor may contribute to the dysfunction observed in schizophrenia, and may affect antipsychotic response. To test this hypothesis, we investigated an amino acid substitution (Arg492Cys) in the 3rd intracellular loop of this g-protein coupled receptor that may alter receptor signal transmission. To test this hypothesis, a total of 123 subjects receiving antipsychotic treatment (110 with schizophrenia, 14 with schizo-affective disorder) and 224 controls, all from northern Spain, were genotyped. Treatment response was assessed prospectively using the Positive And Negative Symptoms Scale (PANSS) and the Global Assessment Scale (GAS). No clear differences were observed between the different groups suggesting that this polymorphism does not have a significant role in either antipsychotic treatment or the aetiology of psychosis.

ASSOCIATION STUDY OF DYSBINDIN GENE (DTBN1) BFAI POLYMORPHISM IN SCHIZOPHRENIA V. De Luca,* R Muglia, M. Masliis, G. Wong, J. L. K e n n e d y

Neurogenetics, Centrefor Addcition and Mental Health, Toronto, ON, Canada Genome-wide linkage scans have provided some replicating evidence for involvement of the region of 6p24-21 in susceptibility to schizophrenia. Recent studies have implicated that the gene DTNBP1 (the human orthologue of the mouse dyshindin gene) in this region is strongly associated with schizophrenia. The purported function of the dysbindin gene in brain development is consistent with the neurodevelopmental hypothesis of schizophrenia. In a case-control association study we investigated the BfaI polymorphism (SNP 909706: an A to G transition) located in intron 1 of the DTNBP1 gene. Our pilot sample size consists of 30 schizophi'enics diagnosed via SCID interview and DSM-1V criteria. These cases are matched with 30 healthy controls for age, gender and ethnicity. The BfaI polymorphism is not associated with schizophrenia in this l~ilot sample (allelewise)~2=1.62, ldf, p=0.27; genotypewise Z~=2.58, 2df, p=0.27). We are cun'ently testing a larger sample of case-controls and a sample of triad families consisting of schizophrenia probands and both parents. In view of the positive genome scan data on 6p and the previously reported strong statistical results for DTNBP1, this gene remains of high interest in schizophrenia. Larger samples and more markers need to be typed at this locus to provide haplotype information and thus a more detailed test of this candidate gene.

COHERENCE OF CO-FAMILIAL PHENOTYPES IN SCHIZOPHRENIA: CRANIOFACIAL DYSMORPHOLOGY, THOUGHT DISORDER, AND SMOOTH PURSUIT EYE MOVEMENTS C. K. Deutsch,* D. L. Levy, E. A. Lauer, O. Krastoshevsky, E. Saunders, M. J. Coleman, S. E Price, S. Matthysse, R S. H o l z m a n

Psychobiology Program, Shriver Center, Waltham, MA, USA We have identified in previous studies three phenotypes that are statistically overrepresented among schizophrenic probands and their relatives: (1) embryologically-derived measures of craniofacial dysmorphology, (2) thought disorder assessed using the TDI, and (3)

7. Genetics, Clinical impairment of smooth pursuit eye movements (SPEM). Among firstdegree relatives, these co-familial traits are more prevalent than schizophrenia itself, and may constitute alternative manifestations of the same pathogenic process(es) that gives rise to psychiatric symptomatology. Our approach to dysmorphology diagnosis combines objective quantitative measures with biological interpretation based on embryologic factors. Both brain and face develop from common primordia (anlagen) and are shaped simultaneously by shared morphogenetic forces. Thus, untoward genetic or teratogenic influences on brain development can also disrupt the formation of craniofacial features. The purpose of this study is to determine the extent to which dysmorphology in schizophenia (here, derivatives of the interface of frontonasal and maxillary primordia) relate to TDI and SPEM scores. We report that dysmorphology and TDI scores are positively correlated among schizophrenic probands; thus, patients who have more anomalies along this embryologic juncture are more severely thought- disordered. This pattern also applies to their firstdegree relatives. However, there is no correlation between dysmorphology and SPEM among schizophrenic probands and relatives. Further, dysmorphology scores were uncorrelated with either behavioral phenotype in contrast groups of bipolar probands and their relatives. Because frontonasal-maxillary dysmorphology predicts specific regions of brain pathogenesis, its correlation with the TDI may advance the biological interpretation of thought disorder. Additionally, these phenotypes may combine with psychiatric diagnoses to boost the power to detect genetic linkage in schizophrenia. (Supported by NIMH: PO1 MH31154, RO1 MH49487, and ROI MH20892.)

AVOIDANT PERSONALITY DISORDER INCREASES THE DETECTION OF FIRST DEGREE RELATIVES AFFECTED BY A SCHIZOPHRENIA SPECTRUM DIAGNOSIS D. L. Fogelson,* K. H. Nuechterlein, R. A. Asarnow, K. L. Subotnik, D. L. Payne, K. C. Jacobson, M. C. Neale, K. S. Kendler

Department of Psychiatry and Biobehavioral Sciences, University of CaliJbrnia Los Angeles, Los Angeles, CA, USA The detection of relatives (Rels) of schizophrenia (Sz) probands who are affected by a Sz spectrum diagnosis (SzSD) allows delineation of an extended phenotype that may be helpful for establishing patterns of famihal transmission. Accepted SzSDs include: Sz, Sz-affective disorder, atypical psychosis, & Sz-typal & paranoid personality disorders. Avoidant Personality Disorder (APD) has been suggested to be a SzSD. APD would increase our detection of Rels "affected by a SzSD if it shows increased rates even when not co-morbid with another SzSD. We examined ifAPD shows heightened rates among Sz Rels, increases the detection of Rels affected by a SzSD, and has an unusual symptom structure. 1° relatives 18 years & older of probands with adult onset Sz (AOS), childhood onset Sz (COS), attention deficit disorder (ADHD), & of adult and child community control probands (ACC & CCC) were blindly interviewed using the DIS, PSE, & SCID. Diagnoses were made using direct interview, family history, & medical records. The risk for APD (see APD frequency Table) using logistic regression corrected for clustering within families, 1 tailed tests, shows: including co-morbid SzSD, (1+2) vs. (3+4), P=.00045; (1+2) vs. (5), P=.046; with no co-morbid SzSD, (1+2) vs. (3+4), P=.0038; (1+2) vs. (5), P=. 13. APD appears 71% of the time (25/35 cases, groups l&2) outside the presence of a SzSD. No significant differences were found between groups in dimen-

International Congress on Schizophrenia Research 2003